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Abstract Metastases are the major cause of cancer-related death, yet, molecular weaknesses that could be exploited to prevent tumor cells spreading are poorly known. Here, we found that perturbing hydrolase transport to lysosomes by blocking either the expression of IGF2R, the main receptor responsible for their trafficking, or GNPT, a transferase involved in the addition of the specific tag recognized by IGF2R, reduces melanoma invasiveness potential. Mechanistically, we demonstrate that the perturbation of this traffic, leads to a compensatory lysosome neo-biogenesis devoided of degradative enzymes. This regulatory loop relies on the stimulation of TFEB transcription factor expression. Interestingly, the inhibition of this transcription factor playing a key role of lysosome production, restores melanomas’ invasive potential in the absence of hydrolase transport. These data implicate that targeting hydrolase transport in melanoma could serve to develop new therapies aiming to prevent metastasis by triggering a physiological response stimulating TFEB expression in melanoma.

Abstract Capecitabine, a pro-drug of 5-fluorouracil, is commonly used in the treatment of breast and colorectal cancer. Its side effects, including nausea, vomiting, diarrhea, fatigue, loss of appetite, and bone marrow suppression, are well recognized. However, coronary vasospasm represents a less commonly recognized but significant complication of fluoropyrimidine-based therapies such as capecitabine. Proposed mechanisms for this adverse effect complication include direct endothelium-independent vasoconstriction, activation of protein kinase C, and activation of the cyclooxygenase pathway. In this report, we present a case of capecitabine-induced coronary vasospasm leading to progressive, focal ST-elevations, myocardial ischemia, and subsequently polymorphic ventricular tachycardia. These events were captured on telemetry, in a male in his early 40s, diagnosed with stage IIIB sigmoid colon cancer. Notably, the patient had no pre-existing coronary artery disease or other cardiovascular risk factors. Upon diagnosis, the patient was initiated on a calcium channel blocker, verapamil, to mitigate further coronary vasospasm events. After thorough discussions that prioritized the patient’s input and values, an implantable cardioverter-defibrillator was placed subcutaneously. Following discharge, the patient restarted capecitabine therapy along with verapamil prophylaxis and did not experience any subsequent shocks from his ICD as assessed during his outpatient follow-up visits. This case emphasizes the need to involve patients in decision-making processes, especially when managing unexpected and serious complications, to ensure treatments align with their quality of life and personal preferences.

Abstract Introduction Lockdown measure has been utilized widely to mitigate COVID-19 pandemic transmission and recently during the 2022 Sudan Ebola Virus Disease outbreak in Uganda. These have setback effects on the continuity of essential health services such as tuberculosis (TB) care, reversing progress made in the fight against tuberculosis (TB) over the past decade. We set out to understand patient-reported barriers to accessing TB care services during the COVID-19 pandemic in Uganda. Methods Mixed methods study involving review of medical records of TB patients who received TB care from January to September 2020. We used quantitative and qualitative methods including phone questionnaires and in-depth interviews. We carried out descriptive statistics, a chi-square test and conducted a thematic analysis. Results We carried out phone interviews with 672 participants. The majority (60%) were male and with an average of 35 years (SD:11). A significantly higher proportion of patients reported a barrier to TB care access during the COVID-19 lockdown than pre-lockdown (79.9% vs. 68.1% p = 0.027). We carried out in-depth interviews with 28 participants (54% (15/28): male). Barriers experienced by these participants included lack of a means of transport to reach the health facility, lack of money to pay the transport fares, long distances to the facility, fear of COVID-19 infection, stigma due to overlap between TB and COVID-19 symptoms, and few health care workers available during the lockdown period. Conclusion Lockdown measures instituted to mitigate the transmission of COVID1-19 affected access to TB care services in Uganda. Uganda is at risk of future emerging and re-emerging diseases of epidemic potential. Therefore, there should be measures to ensure the continuity of essential services such as tuberculosis care during the implementation of future epidemic response interventions such as a lockdown.

Abstract Background Diffuse pleural mesothelioma (DPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear factor-κB (NF-κB) and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair. Methods We used DPM cell lines, murine models (xeno- and allo-grafts), plus DPM patient samples to characterize anti-tumor effects of CBL0137 and to delineate specific molecular mechanisms. Results We verified that CBL0137 induced cell cycle arrest and apoptosis. We also discovered that DPM is a FACT-dependent cancer with overexpression of both subunits structure-specific recognition protein 1 (SSRP1), a poor prognosis indicator, and suppressor of Ty 16 (SUPT16H). We defined several novel uses of CBL0137 in DPM therapy. In combination with cisplatin, CBL0137 exhibited additive anti-tumor activity compared to monotherapy. Similarly, CBL0137 (systemic) could be combined with other novel agents like microRNA-215 (intrapleural) as a more effective regimen. Importantly, we established that CBL0137 induces immunogenic cell death that contributes to activating immune response pathways in DPM. Therefore, when CBL0137 is combined with dual immune checkpoint inhibitors DPM tumor growth is significantly suppressed. Conclusions We identified an unrecognized molecular vulnerability of DPM based on FACT dependency. CBL0137 alone and in several combinations with different therapeutics showed promising efficacy, including that of improved anti-tumor immunity. Overall, these preclinical findings suggest that CBL0137 could be ideally suited for use in DPM clinical trials.

[This corrects the article DOI: 10.1371/journal.pone.0234651.].

IntroductionThe first cells affected by UVB exposure are epidermal keratinocytes, and p53, the genome guardian, is activated in these cells when skin is exposed to UVB. UVB exposure induces appetite, but it remains unclear whether p53 in epidermal keratinocytes plays a role in this appetite stimulation.ResultsHere we found that food intake was increased following chronic daily UVB exposure in a manner that depends on p53 expression in epidermal keratinocytes. p53 conditional knockout in epidermal keratinocytes reduced food intake in mice upon UVB exposure.MethodsTo investigate the effects of p53 activation following UVB exposure, mice behavior was assessed using the staircase, open-field, elevated-plus maze, and conditioned-place preference tests. In addition to effects on appetite, loss of p53 resulted in anxiety-related behaviors with no effect on activity level.DiscussionSince skin p53 induces production of β-endorphin, our data suggest that UVB-mediated activation of p53 results in an increase in β-endorphin levels which in turn influences appetite. Our study positions UVB as a central environmental factor in systemic behavior and has implications for the treatment of eating and anxiety-related disorders.

Introduction: Aortobifemoral bypass is the standard recommended procedure for aortoiliac occlusive disease (AIOD). Patients of AIOD presenting with claudication pain and tissue loss require revascularization of lower limbs, with few requiring mesenteric and/or renal revascularization. Aim: The aim of this study was to assess the outcomes of patients undergoing aortobifemoral bypass with mesenteric/renal revascularization in patients of AIOD with mesenteric/renal occlusion. Objective: The objectives of this study were as follows: (1) restoration of normal renal function in terms of urine output and renal function test in patients who underwent mesenteric revascularization and (2) resolution of abdominal angina in patients who underwent mesenteric revascularization. Methods: A total of 13 patients with a mean age of 45.8 years, presenting with critical limb ischemia with renal/mesenteric occlusion due to AIOD of Trans-Atlantic Inter-Society Consensus D type, underwent aortobifemoral bypass with renal/mesenteric revascularization. The demographics of patients, Rutherford stage and WIFI stage, pre- and postoperative ABI, probable etiology, any renovisceral interventions done, duration of procedure, type of renal ischemia (warm/cold), duration of renal ischemia, postoperative complications, duration of stay, patency of graft, wound infection, amputation rates, and mortality were documented on a structured pro forma. Five (38.46%) patients presented with severe claudication, 3 (23.07%) patients with rest pain, and the remaining 5 (38.46%) patients with minor tissue loss. Along with AIOD, 3 (23.07%) patients had concomitant bilateral femoropopliteal disease and tibial vessel disease, 3 (23.07%) patients had unilateral femoropopliteal disease, and 2 (15.38%) patients had bilateral tibial vessel disease. Three (23.07%) patients had infrarenal aortoiliac occlusion and 10 (76.9%) patients had juxtarenal aortoiliac occlusion (managed using Liddicoat/Madiba–Robbs technique). Outcomes were assessed in terms of graft patency, need of dialysis in postoperative period, wound infection, limb survival, amputations, and mortality. Results: Aortic clamp was placed suprarenal (38.46%), infrarenal (53.84%), and interrenal (7.69%) of patients. Cold renal perfusion solution was used in 15.38% of patients with an ischemia time of 38.5 min. The average duration of warm renal ischemia was 5 min 24 s. Revascularization of superior mesenteric artery (SMA) was done in 15.38%, and inferior mesenteric artery in 38.46%. Renal revascularization by Madiba–Robbs technique was done in 30.76% of patients. In 92.3% of patients, bifurcated Dacron synthetic graft was used, and in 7.69%, femoral vein with bovine pericardial patch was used for revascularization. In postoperative period, 7.69% developed acute limb ischemia, 30.07% had severe metabolic acidosis, and 15.38% of patients had respiratory complications with good renal function and no bowel ischemia. Conclusion: Renal and mesenteric revascularization in addition to aortobifemoral bypass is a safe, effective, and durable procedure with acceptable postoperative complications. The effective surgical technique of renal and mesenteric revascularization including the usage of renal perfusion solution was found to be of paramount importance in our study. All patients who underwent SMA revascularization were free from abdominal angina. All patients who underwent renal revascularization were free from dialysis and also there was a decrease in the use of antihypertensive drugs in these patients.

Background: Mycotic aortic aneurysm of the abdominal aorta is a rare entity. Repair of infected aneurysms is challenging because of the deleterious consequences of the usage of prosthetic material as an arterial conduit with limited availability of autogenous grafts. Aortic graft infection is one of the most morbid complications in vascular surgery. The main objective in treating aortic graft infection is to remove the infected graft material, thoroughly debride, and re-establish the vascular continuity. Neo-Aortoiliac system operation utilizes the femoropopliteal vein in various configurations, depending on the extent of infection and the availability of the conduit. Aim: This article aims to report our experience of various configurations of Neo aortoiliac system operation and various conduits used along with femoropopliteal vein, when the femoropoliteal vein is inadequate. Materials and Methods: The study was performed in a single tertiary care center. Between January 2022 and June 2023, 4 cases of Neo aortoiliac system operation were performed. The demographics, clinical presentation, operative data, and postoperative outcomes were subsequently collected and analysed. Results: 3 out 4 patients of Neo-Aortoiliac system operation survived, one patient had Major Adverse Limb Event and one patient succumbed to death due to sepsis.

Introduction: The biceps brachii muscle takes its name from its two proximally attached ‘heads’. On rare occasions, an anomalous third head arises from the superomedial part of the brachialis and is attached to the bicipital aponeurosis and the medial side of the tendon of insertion. The slip frequently descends in front of and behind the brachial artery and often causes compression of the median nerve or brachial artery. Aim: To calculate incidence of the supernumerary third head of the biceps brachii along with its incidence, anatomical and morphological variations to establish its clinical significance. Materials and Methods: The observational study was conducted in Department of Anatomy, Dr. Kiran C Patel Medical College and Research Institute, Bharuch, Gujarat, India, from October 2021 to September 2022. It included 32 cadaveric upper limbs- 16 right-sided and 16 left-sided. The morphometric measurements were done with the use of digital vernier caliper. The findings were photographed and recorded and the mean and standard deviation were hereby presented and analysed by Statistical Package for Social Sciences (SPSS) version 19.0. Results: The biceps brachii was constituted of supernumery third head in three (9.375%) limbs, one on the right and two on the left-side. In all cases, third head arose from the anteromedial aspect of the mid-humeral shaft; medial to the brachialis and inserted together with the other two heads of the biceps into bicipital aponeurosis and radial tuberosity. The mean length and mean width of the supernumerary head was measured as 141.16±43.63 mm, 25.22±4.99 mm, respectively. A significant difference was not found when compared for symmetrical sides. Conclusion: Three specimen of upper limb were observed with distinct occurrence for the third head with the incidence of 9.37% and predominance on the left-side. In case of various arm surgical procedures knowledge can be used to avoid injuries.

Introduction: The nerve to mylohyoid is a branch of inferior alveolar nerve which arises just above the mandibular foramen. There is occasionally communicating branch between nerve to mylohyoid and lingual nerve. Knowledge of such variations has significance during oral and submandibular surgery. Aim: To detect and describe the existence and occurrence of anatomical variations in the innervation pattern of the nerve to mylohyoid by using the dissection technique. Materials and Methods: An observational study was carried out from January 2022 to April 2022 in a total of 15 embalmed and formalin-fixed cadavers in the Laboratory of Anatomy of SMBT Medical College, Nashik, Maharashtra. The nerve to the mylohyoid and lingual nerve were cleared and observed for any unusual communication between the two, if any. Results: In 13 (86.67%) cadavers, classical (normal) anatomical presentation of the nerve to mylohyoid was observed, whereas, in two male (13.33%) cadavers, the presence of communicating branch between the nerve to mylohyoid and lingual nerve was observed. In both the cadavers, the communicating branch was unilateral, in one cadaver on the right-side, and in the second cadaver same variation was noted on the left-side. Conclusion: The existence of communication between the nerve to mylohyoid and the lingual nerve is thought to be responsible for inadequate mandibular anesthesia. Through this study, surgeons will be aware of this variance, to explain unexpected findings in nerve injury following oral procedures.

Abstract Prolonged steroid treatment has a suppressive effect on the immune system, however, its effect on the cellular response to mRNA vaccine is unknown. Here we assessed the impact of prolonged steroid treatment on the T-cell and humoral response to the SARS-CoV-2 spike (S) peptide following the third dose of the BNT162b2 vaccine in systemic autoimmune rheumatic disease patients. We found that CD4 T-cell response to the S peptide in patients on high-dose long-term steroid treatment showed significantly less S-peptide specific response, compare to low-dose or untreated patients. Remarkably, these results were not reflected in their humoral response, since almost all patients in the cohort had sufficient antibody levels. Moreover, S-peptide activation failed to induce significant mRNA levels of IFNγ and TNFα in patients receiving high-dose steroids. RNA-sequencing datasets analysis implies that steroid treatments' inhibitory effect of nuclear factor kappa-B signaling may interfere with the activation of S-specific CD4 T-cells. This reveals that high-dose steroid treatment inhibits T-cell response to the mRNA vaccine, despite having sufficient antibody levels. Since T-cell immunity is a crucial factor in the immune response to viruses, our findings highlight the need for enhancing the efficiency of vaccines in immune-suppressive patients, by modulation of the T-cell response.

Objective: Numerous studies associate metabolic syndrome (MetS) with poor life quality, depression, and anxiety. Aerobic exercise training has proven its value in promoting health among subjects with MetS. We aimed to evaluate the changes in health-related quality of life (HRQOL), motivation for physical activity, and the levels of anxiety and depression in subjects with MetS after individualized aerobic training. Methods: A total of 140 subjects with MetS (53.2 ± 6.8 years, 55% female) were analyzed after the random assignment to the intervention (n = 84) or the control group (n = 56). Only the intervention group participated in the 8-week HR targeted aerobic training program, which consisted of exercises on a cycle ergometer for 30‑40 min/day, 5 days/week. In all study participants HRQOL, motivation for physical activity, anxiety and depression levels were evaluated by the Medical Outcomes Study 36-Item Short-Form Health Survey, the Exercise Motivations Inventory-2, and the Hospital Anxiety and Depression scale before and after 8 weeks. Results: After 8 weeks, self-reported physical functioning significantly increased only in the intervention group (p = 0.01). The scores of mental health-summary and role limitations due to emotional problems also improved in subjects with MetS, who participated in the aerobic training program (p < 0.001, p = 0.009, respectively). The scores for social engagement motive, enjoyment and revitalization motive, and fitness motive to exercise increased (p = 0.003, p < 0.001, p = 0.023, respectively), whereas the level of depression reduced only in the intervention group (p = 0.021). Conclusions: The 8-week individualized aerobic training had a positive effect on HRQOL, motivation for physical activity, and the level of depression in subjects with MetS.

Abstract Background There is no universally accepted treatment for patients with advanced papillary renal cell carcinoma (PRCC). The presence of activating mutations in MET, as well as gain of chromosome 7, where the MET gene is located, are the most common genetic alterations associated with PRCC, leading to the clinical evaluation of MET tyrosine kinase inhibitors (TKIs) in this cancer. However, TKIs targeting MET selectively, as well as multitargeted TKIs with activity against MET demonstrate modest efficacy in PRCC and primary and secondary treatment failure is common; other approaches are urgently needed to improve outcomes in these patients. Methods High throughput screening with small molecule libraries identified HSP90 inhibitors as agents of interest based on antitumor activity against patient derived PRCC cell lines. We investigated the activity of the orally available HSP90 inhibitor, SNX2112 in vitro, using 2D/3D PRCC cell culture models and in vivo, in mice tumor xenograft models. The molecular pathways mediating antitumor activity of SNX2112 were assessed by Western blot analysis, Flow cytometry, RNA-seq analysis, Real Time qPCR and imaging approaches. Results SNX2112 significantly inhibited cellular proliferation, induced G2/M cell cycle arrest and apoptosis in PRCC lines overexpressing MET. In contrast to TKIs targeting MET, SNX2112 inhibited both MET and known downstream mediators of MET activity (AKT, pAKT1/2 and pERK1/2) in PRCC cell lines. RNAi silencing of AKT1/2 or ERK1/2 expression significantly inhibited growth in PRCC cells. Furthermore, SNX2112 inhibited a unique set of E2F and MYC targets and G2M-associated genes. Interestingly, interrogation of the TCGA papillary RCC cohort revealed that these genes were overexpressed in PRCC and portend a poor prognosis. Finally, SNX-2112 demonstrated strong antitumor activity in vivo and prolonged survival of mice bearing human PRCC xenograft. Conclusions These results demonstrate that HSP90 inhibition is associated with potent activity in PRCC, and implicate the PI3K/AKT and MEK/ERK1/2 pathways as important mediators of tumorigenesis. These data also provide the impetus for further clinical evaluation of HSP90, AKT, MEK or E2F pathway inhibitors in PRCC. Graphical Abstract

IntroductionCardiac shock-wave therapy (CSWT) is a non-invasive regenerative treatment method based on low-frequency ultrasound waves, which stimulate angiogenesis. Current data about the effects of revascularization procedures on angiogenesis biomarkers is limited. Recently, an association of catestatin and endocan with coronary collateral development was shown in several trials. In this study, we aimed to evaluate the impact of CSWT on the dynamics of catestatin and endocan levels and to assess their correlation with parameters of myocardial perfusion and function.MethodsProspective, randomized, triple-blind, sham procedure-controlled study enrolled 72 adult subjects who complied with defined inclusion criteria (NCT02339454). We measured biomarkers in 48 patients with stable angina (24 patients of CSWT group, 24 patients of sham-procedure group). Additionally, patients were divided into responders and non-responders according to improvement in myocardial perfusion and/or contractility assessed by myocardial scintigraphy and dobutamine echocardiography (30 and 13 patients, respectively). The blood samples were collected at baseline, after the last treatment procedure (9th treatment week) and at 6-month follow-up to evaluate biomarkers concentration and stored at –80° until analysis. Serum catestatin and endocan levels were determined by commercially available ELISA kits.ResultsSerum catestatin concentration significantly increased in all patients. While endocan levels significantly decreased in the responders sub-group. The increase in catestatin levels at 9th week and 6 months was positively associated with improvement in summed difference score (rho = 0.356, p = 0.028) and wall motion score, WMS (rho = 0.397, p = 0.009) at 6 months in the whole study population. Meanwhile, the decrease in endocan levels over 6 months was positively correlated with improvement in WMS at 3- and 6- months (r = 0.378, p = 0.015 and r = 0.311, p = 0.045, respectively). ROC analysis revealed that a change at 6 months in catestatin and endocan levels significantly predicted improvement in myocardial perfusion and contractile function with 68.9% sensitivity and 75.0% specificity (p = 0.039) and 51.7% sensitivity, and 91.7% specificity (p = 0.017), respectively. Baseline endocan concentration and its change at 6 months predicted response to CSWT with 68.8% sensitivity and 83.3% specificity (p = 0.039) and 81.3% sensitivity and 100% specificity (p < 0.0001), respectively.ConclusionThis study demonstrates the association of increase in catestatin and decrease in endocan levels with the improvement of myocardial perfusion and contractile function. The potential predictive value of catestatin and endocan dynamics for the response to regenerative therapy is shown.

Patients with injection drug use can have nonthrombotic pulmonary emboli (NTPE) of foreign insoluble particles that are either parts of the equipment used or mixed with the drug as an additive. These foreign particles can become a nidus for infection and inflammation. We present a case of a 31-year-old man with active intravenous drug use who initially presented with signs and symptoms of pleurisy and was found to have NTPE of septic refractile crystalline material as seen on bronchial wash and brush biopsy. We believe our patient likely had embolism of either crack particles, needle fragments or cotton-wool fragments that led to a localized inflammatory reaction and infection. This highlights the importance of obtaining detailed history and diagnostic workup. Once the diagnoses of bacterial endocarditis and thrombophlebitis are ruled out with blood cultures, transthoracic echocardiogram, trans-esophageal echocardiogram and/or CT scan (depending on the suspicion), NTPE should be considered and bronchoscopy with bronchoalveolar lavage with biopsy should be performed.

BackgroundDuring the COVID-19 pandemic, TB mortality increased while diagnoses decreased, likely due to care disruption. In March, 2020, Uganda-a country with high TB burden, implemented a COVID-19 lockdown with associated decrease in TB diagnoses. This study aims to examine patient level risk factors for disruption in TB care during the COVID-19 pandemic in Uganda. This retrospective cross-sectional cohort study included six TB clinics in Uganda. Clustered sampling included phases of TB care and three time-periods: pre-lockdown, lockdown and post-lockdown. Characteristics of patients with TB care disruption (TBCD), defined as those with > 2 months of symptoms prior to diagnosis or who missed a TB clinic, and those without TB care disruption (non-TBCD) were analyzed between time-periods. 1,624 charts were reviewed; 1322 were contacted, 672 consented and completed phone interview; pre-lockdown (n = 213), lockdown (n = 189) and post-lockdown (n = 270). TBCD occurred in 57% (385/672) of patients. There was an increase in the proportion of urban patients in the TBCD and non-TBCD groups during post-lockdown (p

Patient-centered care is recognized as a key element in recent healthcare management strategies. However, the integrated collection of patient feedback capturing the entire journey of patients with complex medical conditions remains understudied. Herein, we aimed to describe the development of an instrument prototype for the collection of PROMs and PREMs that would encompass a whole patient journey at a single time point. We further describe the process of its integration into a hospital’s information system (HIS) and the results of a pilot feasibility study in adult patients with kidney and hematological diseases. We developed an instrument consisting of original PREM and generic EQ-5D-5L questionnaires. E-questionnaires were handled with REDCap software (version 12.5.14) and integrated into the HIS. Patients refusing to use e-questionnaires (48%) were offered paper administration and were older (64 vs. 50 years). The overall response rate for e-questionnaires was 57.1% with a median completion time of 2.0 and 3.7 min for PROM and PREM, respectively. Psychological and social services and primary care setting (diagnosis establishment and involvement in continuous care) were identified as most problematic. The majority of PREM dimensions encompassing different levels of care significantly correlated with PROM responses. Our data indicate the feasibility and potential relevance of the proposed approach, although wider-scale studies in diverse settings are needed.

We aimed to explore the feasibility and potential relevance of integrated electronic collection of patient-reported outcome and experience measures (PROM and PREM) in children with special healthcare needs (CSHCN) by using the example of children with kidney and hematological diseases. We performed a cross-sectional, single-center study of children

Background: High-risk patients undergoing elective surgery are at risk for perioperative complications, including readmissions and death. Advance care planning (ACP) may allow for preparation for such events. Objectives: (1) To assess the completion rate of advance directives (ADs) and their association with one year readmissions and mortality (2) to examine clinical events for decedents. Design: This is an observational cohort study conducted through chart review. Setting/Subjects: Subjects were 400 patients undergoing preoperative evaluation for elective surgery at two hospitals in the United States. Measurements: The prevalence of ADs at the time of surgery and at one year, readmissions, and mortality at one year were determined. Results: Three-hundred ninety patients were included. In total, 102 (26.4%) patients were readmitted, yet did not complete an AD. Seventeen (4.4%) patients filed an AD during follow-up. Nineteen patients died and mortality rate was 4.9%. There was a significant association between completing an AD before death. Of the decedents, seven (37%) underwent resuscitation, but only four had ADs. Conclusions: Many high-risk surgical patients would benefit from ADs before clinical decline. Preoperative clinics present a missed opportunity to ensure ACP occurs before complications arise.

Background American Thoracic Society/European Respiratory Society guidelines recommend context-specific exposure assessments to diagnose interstitial lung disease (ILD). In sub-Saharan Africa, ILD diagnoses are rare, and locally validated ILD exposure questionnaires are not used. Methods A physician-administered ILD exposure questionnaire was developed using a four-step mixed-methods modified Delphi approach. First, ILD questionnaires from high-income countries and data from Pneumotox were reviewed, compiled and face-validated. Second, a local pilot group of ILD experts ranked item relevance using a Likert scale and suggested additions. Third, the questionnaire format and pilot rankings were addressed in a focus group discussion that was analysed using grounded theory. Finally, following focus group discussion modifications, the resulting items (with three duplicate item groups for evaluation of internal consistency) were ranked for importance by members of the Pan-African Thoracic Society (PATS). Results Face validation resulted in 82 items in four categories: “Smoking and Drugs”, “Environmental Exposures”, “Occupations” and “Medications”. Pilot group (n=10) ranking revealed 27 outliers and 30 novel suggestions. Focus group (n=12) discussion resulted in 10 item deletions, 14 additions and 22 re-wordings; themes included desire for extensive questionnaires and stigma sensitivity. Final validation involved 58 PATS members (mean±sd age 46±10.6 years, 76% male, from 17 countries) ranking 84 items derived from previous steps and three duplicate question groups. The questionnaire was internally consistent (Cronbach's α >0.80) and ultimately included 73 items. Conclusion This mixed-methods study included experts from 17 countries in sub-Saharan Africa and successfully developed a 73-item ILD exposure questionnaire for sub-Saharan Africa. African pulmonary experts valued region-specific additions and ranked several items from existing ILD questionnaires as unimportant.

Abstract Background The development of metabolic syndrome (MS) augments risk for atherosclerotic cardiovascular disease (CVD), but pathophysiological mechanisms of this relation are still under discussion. Overlapping CVD risk factors make it difficult to assess the importance of individual elements. This study aimed to analyze subclinical atherosclerosis based on arterial structure and function parameters in patients with MS and different triglycerides levels. Methods Patients (aged 40–65 years) were divided into two groups: patients with MS and with or without hypertriglyceridemia (hTG). Noninvasive assessment of vascular parameters—aortic augmentation index adjusted for heart rate 75 bpm (AIxHR75), pulse wave velocity (PWV), and common carotid artery intima-media thickness (cIMT) were performed. Results Carotid-femoral PWV (cfPWV) and carotid-radial PWV (crPWV) were significantly higher in patients with hTG. After adjusting for age, gender, waist circumference, fasting glucose, smoking status, cardiovascular family history and mean arterial pressure, crPWV (OR 1.150; CI 95% 1.04–1.28), cfPWV (OR 1.283; CI 95% 1.14–1.42) and cIMT (OR 1.13; CI 95% 1.02–1.25) were significantly associated with hTG (p

Abstract Background MASK‐air® is an app whose aim is to reduce the global burden of allergic rhinitis (AR) and asthma. A transfer of innovative practices was performed to disseminate and implement MASK‐air® in European regions. The aim of the study was to examine the implementation of the MASK‐air® app in Lithuanian adults in order to investigate (i) the rate of acceptance in this population, (ii) the duration of app use and (iii) the evaluation of the app after its use. Methods In a longitudinal study, Lithuanian adults with AR and/or asthma were recruited by allergists. They were informed about how to use MASK‐air® and were followed closely. They were reviewed after one to 3 months to evaluate satisfaction and were asked to continue using the app. Results Among the 149 patients recruited (37.2 ± 10.4 years), 52.4% had rhinitis alone, 42.9% had rhinitis, asthma and/or conjunctivitis multimorbidity, and 2.7% isolated asthma. According to the MASK‐air® baseline questionnaire, 88.3% of patients considered that their symptoms were troublesome. Data were available for 102 (68.4%) patients. The duration of app usage in patients ranged from 1 to 680 days (median, 25–75 percentile: 54, 23.2–151 days). Forty‐two (41.1% of patients who were reviewed) patients agreed to share their opinion on MASK‐air®. Most users of the app were satisfied, from 46.5% thinking their allergy was treated more successfully to 90.4% recommending this app to other allergy sufferers. Discussion When recommended by physicians, MASK‐air® was used for a longer period of time.

Despite the remarkable successes of cancer immunotherapies, the majority of patients will experience only partial response followed by relapse of resistant tumors. While treatment resistance has frequently been attributed to clonal selection and immunoediting, comparisons of paired primary and relapsed tumors in melanoma and breast cancers indicate that they share the majority of clones. Here, we demonstrate in both mouse models and clinical human samples that tumor cells evade immunotherapy by generating unique transient cell-in-cell structures, which are resistant to killing by T cells and chemotherapies. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and disseminate into single tumor cells once T cells are no longer present. This formation is mediated predominantly by IFNγ-activated T cells, which subsequently induce phosphorylation of the transcription factors signal transducer and activator of transcription 3 (STAT3) and early growth response-1 (EGR-1) in tumor cells. Indeed, inhibiting these factors prior to immunotherapy significantly improves its therapeutic efficacy. Overall, this work highlights a currently insurmountable limitation of immunotherapy and reveals a previously unknown resistance mechanism which enables tumor cells to survive immune-mediated killing without altering their immunogenicity.

Type 2 diabetes (T2D) is associated with obesity and declining β-cells. L-glutamine has been implicated in the amelioration of T2D by virtue of its incretin secretagogue property while, there are mixed reports on pitavastatin’s adiponectin potentiating ability. We aimed to investigate the effect of pitavastatin (P), L-glutamine (LG), and combination (P + LG) on glycemic control and β-cell regeneration in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2D mouse model. C57BL6/J mice treated with HFD + STZ were divided into four groups: diabetes control (HFD + STZ), P, LG, and P + LG, while the control group (NCD) was fed with the normal-chow diet. Significant amelioration was observed in the combination therapy as compared to monotherapies in respect of (i) insulin resistance, glucose intolerance, lipid profile, adiponectin levels, and mitochondrial complexes I, II, and III activities, (ii) reduced phosphoenolpyruvate carboxykinase, glucose 6-phophatase, glycogen phosphorylase, and GLUT2 transcript levels with increased glycogen content in the liver, (iii) restoration of insulin receptor 1β, pAkt/Akt, and AdipoR1 protein levels in skeletal muscle, and (iv) significant increase in islet number due to β-cell regeneration and reduced β-cell death. L-glutamine and pitavastatin in combination can ameliorate T2D by inducing β-cell regeneration and regulating glucose homeostasis.

Malignant pleural mesothelioma (MPM) is an incurable surface neoplasm with peculiar pathobiology. MPM proliferates by using the tyrosine-kinase-Ras pathway. Despite representing an attractive therapeutic target, there are no standard agent(s) specifically inhibiting Ras signaling adopted in clinical settings. We posited that biologic effects of microRNA (miRNA) can disrupt this molecular network. Using patient samples, cell lines, and murine tumor xenograft models, we confirmed specific genes in the Ras pathway are targeted by an MPM-associated miRNA and then examined its therapeutic effects. We verified significant and consistent downregulation of miR-206 in MPM tissues. When miR-206 is ectopically re-expressed in MPM cells and delivered to tumor xenografts in mice, it exerted significant cell killing by suppressing multiple components of the receptor-tyrosine-kinase-Ras-cell-cycle-signaling network; some of which were prognostic when overexpressed and/or have not been druggable. Of note, we validated CDK6 as a novel target of miR-206. Overall, this miR-206-targeting mechanism manifested as induced G1/S cell cycle arrest. In addition, we identified a novel MPM therapeutic combination by adding systemic-route abemaciclib with local-route miR-206, which showed additive efficacy translating to improved survival. Our pre-clinical study suggests a potential pathophysiologic role for, and therapeutic relevance of, miR-206 in MPM.

Patient-reported measures are useful in the public interest to improve the quality of care and to assess patients’ needs and priorities by helping to identify existing barriers. A bibliometric analysis was carried out to investigate the use and relevance of patient-reported measures in other countries, which showed the growth of the topic in the scientific literature and allowed the identification of the most important integration processes. Patient-reported measures have been implemented in the information system of Vilnius University Hospital Santaros Clinics and a pilot study with real patients is planned for the future to evaluate the results and propose how this system could be integrated into the Lithuanian eHealth system. Article in Lithuanian. Pacientų įtraukties įrankių integravimas į ligoninės informacinę sistemą: bibliometrinė analizė ir atvejo tyrimas Santrauka Pacientų įtraukties įrankiai yra naudingi viešajam interesui, siekiant gerinti sveikatos priežiūros kokybę ir įvertinti pacientų poreikius bei prioritetus, nes padeda nustatyti esamas kliūtis. Siekiant išsiaiškinti pacientų įtraukties įrankių naudojimą ir aktualumą kitose valstybėse, buvo atlikta bibliometrinė analizė, kuri parodė temos plėtojimąsi mokslinėje literatūroje ir leido identifikuoti svarbiausius integravimo procesus. Vilniaus universiteto ligoninės Santaros klinikų informacinėje sistemoje buvo įdiegti pacientų įtraukties įrankiai ir ateityje planuojama atlikti bandomąjį tyrimą su realiais pacientais, įvertinti rezultatus ir pasiūlyti, kaip ši sistema galėtų būti integruota į Lietuvos e. sveikatos sistemą. Reikšminiai žodžiai: elektroniniai sveikatos įrašai, kokybė, pacientų įtraukties įrankiai, e. sveikata, bibliometrinė analizė.

Abstract Background COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HICs), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting. Methods LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in Central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years, (2) full-time resident of the study area, (3) daily biomass exposure, (4) post-bronchodilator FEV1/FVC below the 5th percentile of the Global Lung Initiative mixed ethnic reference population, and (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George’s Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every 6 months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP), and theophylline levels at baseline, 1 month, and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D. Trial registration ClinicalTrials.gov NCT03984188 . Registered on June 12, 2019 Trial acronym Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD)

Background: In papillary thyroid carcinoma (PTC), BRAFV600E is a common mutation and is associated with aggressive clinical behaviour. Immunocytochemistry (ICC) and molecular testing are recommended in the Bethesda System for Reporting Thyroid Cytopathology 2017 (TBSRTC) category III, IV and V. Aims: The current study aimed to evaluate the diagnostic efficacy of conventional FNAC versus FNAC with BRAFV600E immunostaining in cases of TBSRTC category IV, cases of suspicious for PTC and cases of PTC. Methods and Material: The study included a prospective case series of 45 patients with clinically palpable thyroid nodules with TBSRTC category IV, category V (suspicious for PTC) and PTC. The corresponding histology specimens of all the 45 cases were also analyzed. Immunostaining for BRAFV600E was performed on FNAC cell blocks and their corresponding histology sections using anti-BRAF (VE1) clone (Ventana). The diagnostic efficacy of the BRAFV600E immunostaining was compared on cytological specimens with histological specimens Results: BRAFV600E immunostaining helped to improve the sensitivity of the cytology to confirm the PTC as a diagnostic aid for thyroid FNAs. Cytology alone had a sensitivity of 62.96% and a lower specificity of 60.70%. The combination of both the tests together provided 84.62% sensitivity and much higher specificity of 100%. PPV was also increased to 100% and NPV was raised 94.12%. Conclusions: The performance of BRAFV600E immunostaining on the cytological specimen is a rapid, simple and cost-effective test and could be considered in TBSRTC category IV and suspicious and malignant cases of PTC.

IntroductionDespite the rising burden of chronic respiratory disease globally, and although many respiratory medications are included in the World Health Organization Essential Medications List (WHO-EML), there is limited information concerning the availability and affordability of treatment drugs for respiratory conditions in low- and middle-income countries (LMICs).MethodsAll public and private pharmacies in catchment areas of the Global Excellence in COPD outcomes (GECo) study sites in Bhaktapur, Nepal, Lima, Peru, and Nakaseke, Uganda, were approached in 2017-2019 to assess pricing and availability of medications for the management of asthma and COPD.ResultsWe surveyed all 63 pharmacies in respective study areas in Nepal (95.2% private), 104 pharmacies in Peru (94.2% private) and 53 pharmacies in Uganda (98.1% private). The availability of any medication for respiratory disease was higher in private (93.3%) compared to public (73.3%) pharmacies. Salbutamol (WHO-EML) monotherapy in any formulation was the most commonly available respiratory medication among the three sites (93.7% Nepal, 86.5% Peru and 79.2% Uganda) while beclomethasone (WHO-EML) was only available in Peru (33.7%) and Nepal (22%). LABA-LAMA combination therapy was only available in Nepal (14.3% of pharmacies surveyed). The monthly treatment cost of respiratory medications was lowest in Nepal according to several cost metrics: the overall monthly cost, the median price ratio comparing medication costs to international reference prices at time of survey in dollars, and in terms of days' wages of the lowest-paid government worker. For the treatment of intermittent asthma, defined as 100 mcg Salbutamol/Albuterol inhaler, days' wages ranged from 0.47 days in Nepal and Peru to 3.33 days in Uganda.ConclusionThe availability and pricing of respiratory medications varied across LMIC settings, with medications for acute care of respiratory diseases being more widely available than those for long-term management.

The wide spectrum of COVID-19 symptoms complicates the selection of target groups for screening. We aimed to compare data of children screened for COVID-19 at the pediatric emergency department in Vilnius between different phases throughout 1 year (Phase I: March–May, 2020; Phase II: June–September, 2020; and Phase III: October, 2020–February, 2021) and to evaluate the possible predictors of the disease. SARS-CoV-2 PCR tests were positive for 2.7% of tested children (248/9,238), significantly higher during the Phase III (5.5%) compared with the Phase I (0.6%, p = 0.000) and Phase II (0.3%, p = 0.000). Infants and teenagers (12–17 years) accounted for a larger proportion of COVID-19 patients (24.6 and 26.2%, respectively) compared to other age groups: 1–2 years (18.9%), 3–6 years (14.9%), and 7–11 years (15.3%). There were more COVID-19 cases among children with a known SARS-CoV-2 exposure compared to those who did not declare any contact (18.2 vs. 1.1%, p = 0000). When symptoms were adjusted for age, gender and known exposure to SARS-CoV-2, we found that fever (OR 2.66; 95% CI 1.89–3.81), pharyngitis (OR 1.35; 95% CI 1.01–1.80), headache (OR 1.81; 95% CI 1.09–2.90), and anosmia/ageusia (OR 6.47; 95% CI 1.61–22.47) were the most significant predictors.Conclusion: Although high numbers of testing were maintained throughout the year, the positive test results were significantly higher during the Phase III. Age (

This project describes the creation of a single searchable resource during the pandemic, called the COVID-19 Best Evidence Front Door, with a primary goal of providing direct access to high-quality meta-analyses, literature syntheses, and clinical guidelines from a variety of trusted sources. The Front Door makes relevant evidence findable and accessible with a single search to aggregated evidence-based resources, optimizing time, discovery, and improved access to quality scientific evidence while reducing the burden of frontline health care providers and other knowledge-seekers in needing to separately identify, locate, and explore multiple websites.

This report discusses the case of a 25-year-old pregnant woman from an underserved community, with two previous failed kidney transplants and a previous miscarriage. The patient required a progressive increase to 30 h a week of in-hospital hemodialysis during the COVID-19 pandemic lockdown. She delivered her baby while transitioning to home hemodialysis. Women with end-stage kidney disease who require hemodialysis and wish to become pregnant or who are pregnant have options to allow for a safe and healthy delivery. This can be achieved with vigorous hemodialysis, even at home.

Background and aims: This study aimed to estimate the prevalence of cardiovascular risk factors in middle-aged Lithuanian men categorized according to body mass index and waist circumference results. Methods and results: The data were from the Lithuanian High Cardiovascular Risk primary prevention program between 2009 and 2016. This community-based cross-sectional study comprised 38,412 men aged 40 to 54 years old. We compared the prevalence of arterial hypertension, dyslipidaemia, diabetes mellitus, smoking, and metabolic syndrome in body mass index (BMI) and waist circumference (WC) groups. Regarding the allometric anthropometrics for WC, A Body Shape Indices (ABSIs) were analyzed with respect to mortality risk and smoking status. The most prevalent risk factor in men was dyslipidaemia, followed by arterial hypertension and smoking (86.96%, 47.94%, and 40.52%, respectively). All risk factors except for smoking were more prevalent in men with overweight or obesity as measured by BMI compared to men with normal weight. Similarly, smoking was the only cardiovascular risk factor that was more prevalent among subjects with normal WC compared to those with increased WC or abdominal obesity. Elevated ABSI, which is associated with higher mortality risk, was more prevalent in smokers. Conclusion: The most prevalent cardiovascular risk factor among middle-aged Lithuanian men was dyslipidaemia, with a surprisingly high prevalence in all BMI and WC groups. Smoking was the only risk factor most prevalent in subjects with low or normal weight according to BMI. It was also more prevalent in the normal WC group compared to the increased WC or abdominal obesity groups, but ABSI values associated with higher mortality were more prevalent among smokers than non-smokers.

Summary: Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions.

To determine the effect of distributed practice (spacing out of study over time) and retrieval practice (recalling information from memory) on academic grades in health professions education and to summarise a range of interventional variables that may affect study outcomes. A systematic search of seven databases in November 2022 which were screened according to predefined inclusion criteria. The Medical Education Research Study Quality Instrument (MERSQI) and Newcastle-Ottawa Scale-Education (NOS-E) were used to critically appraise eligible articles. A summary of interventional variables includes article content type, strategy type, assessment type and delay and statistical significance. Of 1818 records retrieved, 56 were eligible for inclusion and included a total of 63 experiments. Of these studies, 43 demonstrated significant benefits of distributed practice and/or retrieval practice over control and comparison groups. Included studies averaged 12.23 out of 18 on the MERSQI and averaged 4.55 out of 6 on the NOS-E. Study designs were heterogeneous with a variety of interventions, comparison groups and assessment types. Distributed practice and retrieval practice are effective at improving academic grades in health professions education. Future study quality can be improved by validating the assessment instruments, to demonstrate the reliability of outcome measures. Increasing the number of institutions included in future studies may improve the diversity of represented study participants and may enhance study quality. Future studies should consider measuring and reporting time on task which may clarify the effectiveness of distributed practice and retrieval practice. The stakes of the assessments, which may affect student motivation and therefore outcomes, should also be considered.

Abstract Background Recent triple-blind sham procedure-controlled study revealed neutral effects of the cardiac shock wave therapy (CSWT) on exercise tolerance and symptoms in patients with stable angina. Current data about the effects of CSWT on global and regional myocardial contractility and perfusion is limited. Hereby we report the results of an imaging sub-study that evaluated the capacity of CSWT to ameliorate myocardial ischemia induced during dobutamine stress echocardiography (DSE) and cardiac single photon emission computed tomography (SPECT). Methods Prospective, randomized, triple-blind, sham procedure-controlled study enrolled 72 adult subjects who complied with defined inclusion criteria. The subjects were assigned to the OMT + CSWT and the OMT + sham procedure study groups with 1:1 ratio. Application of the CSWT covered all segments of the left ventricle. Imaging ischemia tests were performed in 59 study patients: DSE and SPECT before the CSWT treatment and after 6 months, with DSE carried out additionally at 3 months after randomization. Co-primary endpoints of the study were: change in wall motion score index (WMSI), representing the stress-induced impairment of regional myocardial function, and change in summed difference score (SDS), representing the amount of perfusion defect. Results OMT + CSWT and OMT + sham procedure study groups included 30 and 29 patients, respectively. Regional myocardial contractility during DSE significantly improved at 3 months follow-up in OMT + CSWT group compared to baseline as shown by WMSI at stress (1.4 ± 0.4 vs 1.6 ± 0.4, p = 0.001), but not in OMT + sham procedure group (1.5 ± 0.3 vs 1.6 ± 0.4, p = 0.136). The difference in stress DSE results between both study groups disappeared after 6 months. SPECT results demonstrated a significant reduction of inducible ischemia in OMT + CSWT group compared to OMT + sham procedure group at 6 months follow-up (SDS dropped from 5.4 ± 3.7 to 3.6 ± 3.8 vs 6.4 ± 5.9 to 6.2 ± 5 respectively, p = 0.034). Conclusions Cardiac shock wave treatment showed the ability to reduce stress-induced myocardial ischemia, as assessed by wall motion abnormalities and perfusion defects, compared to sham procedure. Trial registration Clinicaltrials.gov (NCT02339454). The trial was registered retrospectively on 12 January 2015.

Purpose: The objective of this study was to assess predictive value of various arterial markers for cardiovascular (CV) events in patients with metabolic syndrome (MetS). Materials and methods: A longitudinal study with the follow-up period of 3.9 ± 1.7 years investigated 2728 middle-aged (53.9 ± 6.2 years old, 63% women) MetS subjects without overt CV disease. The study cohort was comprised of the participants of the Lithuanian High Cardiovascular Risk primary prevention program. The baseline assessment included the evaluation of brachial flow-mediated dilatation (FMD), carotid intima-media thickness (cIMT), carotid stiffness index, aortic pulse wave velocity (aPWV), aortic augmentation index (AIx), and cardio-ankle vascular index). The data on the cardiovascular outcome (fatal or non-fatal myocardial infarction or stroke) was collected by using the databases of the two major national registries. Results: Over the follow-up period, 83 (3%) patients had at least one cardiovascular event. In a univariate analysis, occurrence of CV events was associated with the following parameters: higher mean blood pressure, aPWV, AIx and cIMT, and lower FMD (all p 794 mcm had higher CV risk (p 11.1 m/s (p = .023). Meanwhile, in patients with cIMT ≤ 794mcm, the FMD cut-off point of 6.5% further stratified the risk (p = .003). Conclusions: In our prospective study, CV risk in the middle-aged patients with MetS was associated with an increase in cIMT and aPWV, and with a decrease in FMD.

Introduction: Anaplastic thyroid cancer (ATC) is rare but fatal thyroid cancer responsible for majority of thyroid cancer related mortality. ATC may originate de novo or from preexisting differentiated thyroid cancer. Complex interaction between different gene mutation has been suggested to be the main causative factor for origin of ATC in both pathways. Mostly affected pathways are MAP kinase and PI3CA kinase. Hence, we decided to study the frequent alterations in both the pathways in ATC patients. Methodology: Clinico-pathological data of 34 ATC patients were collected retrospectively and Formalin Fixed Paraffin Embedded (FFPE) blocks were taken out for genetic analysis. DNA and RANA were isolated from FFPE tissues. BRAF V600E mutations were screened by RFLP PCR method and confirmed by sequencing. RAS, PI3CA and p53 mutations were checked by sequencing. RET/PTC translocations were screened by Real Time PCR. Results: A total of 34 patients were studied: Mean age 58.6+ 11.6 years with F:M- 1.8:1, 60% had history of goiter. Most common presenting symptom was rapidly growing thyroid mass followed by dyspnea, dysphasia and hoarseness of voice. Extent of disease was local, locoregional and metastatic in 32%, 35% and 33% respectively. 57.6% were euthyroid, 20.5 % were hyperthyroid while functional status were not available in 11.7%. FNAC was suggestive of ATC only in 52.9% cases. 15 (44%) were operated. BRAF V600E mutations were observed in 10/34 (29.4%). Interestingly, all three ATC patients with DTC components had previous history of goiter with rapid increase in size and BRAF V600E mutation, while BRAF was positive only in 7/31 (22.5%) of patients with no DTC component. Mean survival of 3.5 months in BRAF positive cases in comparison to 5.5 months in BRAF negative ATC. RAS mutations were found to be positive in 5.8%, and none had RET-PTC/PI3CA mutations. P53 mutation was positive in 7 patients. 3 patients presented with history of rapid increase in size of previous goiter while rest 4 patients presented with rapidly increasing thyroid swelling of 1 to 3 months. At presentation 2 patients has disease localized to thyroid, 4 has loco-regional disease and one patient presented with metastasis. 5 out of these 7 patients were operated (Total thyroidectomy:3, thyroidectomy with neck dissection:2). Mean survival was 4 months (1-6 months). Conclusion: BRAF V600E was the commonest mutation followed by p53 of the 5 genes tested and BRAF was more common in patients with previous history of longstanding goiter or differentiated thyroid cancer. This provides an indirect evidence of neoplastic transformation of PTC to ATC.

Introduction: The cure rate after focused parathyroidectomy (FP) is dependent upon two critical adjuncts- concordant preoperative imaging and intraoperative parathyroid hormone (PTH), a technique which can reliably determine whether any other hyperfunctioning gland or glands are still present after resection of the lesion shown by imaging. We wanted to see the cure rate of FP by using these two adjuncts. We also sought to discern whether utilizing the central lab rapid PTH assay will lead to wider acceptance of this FP with intraoperative PTH in resource-constrained countries. This analysis was also undertaken to find out cost-effective way of doing intraoperative PTH by minimizing the samples for intraoperative PTH study. Result: Data were collected on 83 patients with sporadic primary hyperparathyroidism (PHPT) who underwent parathyroidectomy in two tertiary centers between '2009 and 2017'. A total of 75 patients had concordant imaging, while seven had discordant imaging. The sensitivity and specificity of intraoperative PTH in FP was 100%. All the 78 patients who had fall in intraoperative PTH (50%) at 10 min also had fall of more than 50% at 5 min except one patient (98.7%). Conclusion: We strongly advocate routine use of intraoperative PTH in all patients undergoing minimally invasive parathyroidectomy, as this adjunct offers maximum safety for the patient and confidence for the surgeon. Cost can be minimized by utilizing the central laboratory and reducing the number of samples.

Von Hippel–Lindau (VHL) disease is an autosomal dominant disorder characterized by various endocrine, nonendocrine, benign, and malignant tumors in various organs. VHL tumor suppressor gene, located on short arm of chromosome 3 is responsible for this. Pheochromocytoma (PCC) is one of the important endocrine manifestations that needs to be ruled out in case of VHL suspicion. In this review, we summarize the endocrine manifestations of VHL disease and their management while giving case history of five such cases.

Abstract Background Currently there is no diabetes-specific quality of life (QOL) instrument available in Lithuanian language. We aimed to develop a Lithuanian version of a widely-used individualised instrument - the Audit of Diabetes Dependent Quality of Life questionnaire (ADDQOL-19) and assess the validity and reliability in patients with type 1 and type 2 diabetes mellitus (DM). Methods This study was conducted at the Primary Care and Endocrinology Outpatient Clinics in Vilnius. The ADDQOL was translated from the original English (UK) into Lithuanian using a standardized methodology of forward and back translation. After cognitive “debriefing” the validity and reliability of LT-ADDQOL questionnaire were assessed in a sample of 138 diabetes patients. Cronbach’s alpha coefficient, factor analysis, independent t tests and ANOVA were used. Results There were 106 participants with type 2 and 32 with type 1 DM included in the study with a mean age of 55.5 years (± 14.5) and 56.2% women. The Cronbach’s alpha coefficient was 0.908 and most of items loading values onto one single factor were larger than 0.40 (varied from 0.41 to 0.77), indicating good internal consistency and reliability of instrument. Conclusions We developed the Lithuanian version of ADDQOL-19 which is a valid and reliable instrument to measure impact of diabetes on QOL. It could be further used by clinicians and researchers for comprehensive assessment of QOL in adults with diabetes.